Methods for the Administration of Certain VMAT2 Inhibitors

1 . A method of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof wherein the patient is also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising:

administering the VMAT2 inhibitor in an amount equivalent to about 40 mg of valbenazine free base once daily to the patient.

2 . A method of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof wherein the patient is also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising:

administering a therapeutically effective amount of the VMAT2 inhibitor to the patient,

wherein the therapeutically effective amount of the VMAT2 inhibitor is less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

3 . A method of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof, comprising:

administering to the patient a therapeutically effective amount of the VMAT2 inhibitor,

subsequently determining that the patient is to begin treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor, and

administering the VMAT2 inhibitor in an amount equivalent to about 40 mg of valbenazine free base once daily to the patient.

4 . A method of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof, comprising:

administering a therapeutically effective amount of the VMAT2 inhibitor to the patient,

subsequently determining that the patient is to begin treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor, and

administering the VMAT2 inhibitor in an amount that is less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

5 . A method of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof wherein the patient is also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising:

administering a therapeutically effective amount of the VMAT2 inhibitor to the patient,

wherein the administration produces a mean valbenazine C max that is about 1 to about 2 fold higher than the mean valbenazine C max for a patient who is not being administered a strong CYP3A4 inhibitor and/or a mean valbenazine AUC 0-∞ that is about 1.5 to about 2.5 fold higher than the mean valbenazine AUC 0-∞ for a patient who is not being administered a strong CYP3A4 inhibitor.

6 . A method of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof to a patient in need thereof wherein patient is also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising:

administering a therapeutically effective amount of the VMAT2 inhibitor,

wherein the administration produces a mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol C max that is about 1 to about 2 fold higher than the mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol C max for a patient who is not being administered a strong CYP3A4 inhibitor and/or a mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol AUC 0-∞ that is about 1.5 to about 2.5 fold higher than the mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol AUC 0-∞ for a patient who is not being administered a strong CYP3A4 inhibitor.

7 . The method of any one of claims 1 to 6 , further comprising informing the patient or a medical care worker that administration of the VMAT2 inhibitor to patients who is also being administered a strong CYP3A4 inhibitor in higher exposure of valbenazine and/or (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol than administration of the VMAT2 inhibitor to a patient who is not being administered a strong CYP3A4 inhibitor.

8 . The method of any one of claims 1 to 7 , further comprising informing the patient or a medical care worker that administration of the VMAT2 inhibitor to a patient who is also being administered a strong CYP3A4 inhibitor may result in increased risk of one or more exposure-related adverse reactions than administration of the VMAT2 inhibitor to a patient who is not being administered a strong CYP3A4 inhibitor.

9 . The method of claim 8 , wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, increase in blood glucose, increase in weight, respiratory infections, drooling, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, increase in prolactin, increase in alkaline phosphatase, and increase in bilirubin.

10 . The method of claim 9 , wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation.

11 . The method of claim 10 , wherein the one or more exposure-related adverse reactions is chosen from somnolence and QT prolongation.

12 . The method of any one of claims 1 to 11 , further comprising informing the patient or a medical care worker that co-administration of the VMAT2 inhibitor and the CYP3A4 inhibitor may prolong the patient's QT interval.

13 . The method of any one of claims 1 to 12 , further comprising informing the patient or a medical care worker that administration of the VMAT2 inhibitor to a patient who is also being administered a strong CYP3A4 inhibitor may prolong the patient's QT interval than administration of the VMAT2 inhibitor to a patient who is also being administered a strong CYP3A4 inhibitor.

14 . The method of any one of claims 1 to 13 , wherein the strong CYP3A4 inhibitor is chosen from clarithromycin, chloramphenicol, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin.

15 . The method of claim 14 , wherein the strong CYP3A4 inhibitor is chosen from clarithromycin, itraconazole, and ketoconazole.

16 . The method of claim 15 , wherein the strong CYP3A4 inhibitor is ketoconazole.

17 . The method of any one of claims 1 to 16 , wherein the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder.

18 . The method of claim 17 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-refractory obsessive compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthocytosis.

19 . The method of claim 18 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

20 . The method of claim 18 , wherein the hyperkinetic movement disorder is tardive dyskinesia.

21 . The method of claim 18 , wherein the hyperkinetic movement disorder is Tourette's syndrome.

22 . The method of claim 18 , wherein the hyperkinetic movement disorder is Huntington's disease.

23 . The method of claim 18 , wherein the hyperkinetic movement disorder is tics.

24 . The method of claim 18 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

25 . The method of claim 18 , wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremors.

26 . The method of any one of claims 1 to 25 , wherein the VMAT2 inhibitor is administered orally.

27 . The method of any one of claims 1 to 26 , wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule.

28 . The method of any one of claims 1 to 27 , wherein the VMAT2 inhibitor is administered with or without food.

29 . The method of any one of claims 1 to 28 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof.

30 . The method of claim 29 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof.

31 . The method of claim 30 , wherein the VMAT2 inhibitor is a valbenazine tosylate salt.

32 . The method of claim 31 , wherein the VMAT2 inhibitor is a ditosylate salt of valbenazine.

33 . The method of claim 29 , wherein the VMAT2 inhibitor is an isotopic variant that is L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof.

34 . The method of any one of claims 1 to 33 , wherein the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base.

35 . The method of claim 34 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base.

36 . The method of claim 34 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base.

37 . The method of claim 34 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base.

38 . The method of claim 34 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base.

39 . The method of claim 34 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base.

40 . The method of any one of claims 1 to 33 , wherein the VMAT2 inhibitor is administered for a first period of time in a first amount and then the amount is increased to a second amount.

41 . The method of claim 38 , wherein the first period of time is a week.

42 . The method of claim 38 or 39 , wherein the first amount is equivalent to about 40 mg of valbenazine free base.

43 . The method of any one of claims 38 to 40 , wherein the second amount is equivalent to about 80 mg of valbenazine free base.

44 . The method of any one of claims 1 to 33 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of (+)-α-DHTBZ of at least 15 ng per mL plasma over an 8 hour period.

45 . The method of any one of claims 1 to 33 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of approximately between about at least 33% -50% of the C max over a 12 hour period.

46 . The method of any one of claims 1 to 33 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)-α-DHTBZ per mL plasma; and (ii) a threshold concentration of at least 15 ng (+)-α-DHTBZ per mL plasma over a period of about 8 hours to about 24 hours.

47 . The method of any one of claims 1 to 33 , wherein the therapeutically effective amount of the VMAT2 inhibitor is 10-90% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

48 . The method of any one of claims 1 to 33 , wherein the therapeutically effective amount of the VMAT2 inhibitor is 20-80% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

49 . The method of any one of claims 1 to 33 , wherein the therapeutically effective amount of the VMAT2 inhibitor is 30-70% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

50 . The method of any one of claims 1 to 33 , wherein the therapeutically effective amount of the VMAT2 inhibitor is 40-60% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

51 . The method of any one of claims 1 to 33 , wherein the therapeutically effective amount of the VMAT2 inhibitor is about 50% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

52 . The method of any one of claims 1 to 28 , wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof.

53 . The method of claim 52 , wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt thereof.

54 . The method of claim 52 , wherein the VMAT2 inhibitor is an isotopic variant that is (+)-α-3-isobutyl-9,10-di(methoxy-d 3 )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

55 . A composition for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising the VMAT2 inhibitor, characterized in that the composition is administered in an amount equivalent to about 40 mg of valbenazine free base of the VMAT2 inhibitor once daily to the patient.

56 . A composition for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising the VMAT2 inhibitor, characterized in that the therapeutically effective amount of the VMAT2 inhibitor is less than the amount that would be administered to a patient who is not being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

57 . A composition for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising the VMAT2 inhibitor,

characterized in that the composition comprising the VMAT2 inhibitor in an amount equivalent to about 40 mg of valbenazine free base is administered once daily to the patient subsequently determined to begin treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor following administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

58 . A composition for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising the VMAT2 inhibitor

characterized in that the composition comprising the VMAT2 inhibitor in an amount that would be less than that administered to a patient who has not begun treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor is administered to the patient subsequently determined to have begun treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor following administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

59 . A composition for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, and being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising:, comprising a therapeutically effective amount of the VMAT2 inhibitor,

wherein administration of the composition produces a mean valbenazine C max that is about 1 to about 2 fold higher than the mean valbenazine C max for a patient who is not being administered a strong CYP3A4 inhibitor and/or a mean valbenazine AUC 0-∞ that is about 1.5 to about 2.5 fold higher than the mean valbenazine AUC 0-∞ for a patient who is not being administered a strong CYP3A4 inhibitor.

60 . A composition for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, and being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising: comprising a therapeutically effective amount of the VMAT2 inhibitor,

wherein administration of the composition produces a mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol C max that is about 1 to about 2 fold higher than the mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol C max for a patient who is not being administered a strong CYP3A4 inhibitor and/or a mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol AUC 0-∞ that is about 1.5 to about 2.5 fold higher than the mean (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol AUC 0-∞ for a patient who is not being administered a strong CYP3A4 inhibitor.

61 . The composition of any one of claims 55 to 60 , wherein the patient or a medical care worker is informed that administration of the composition to patients who is also being administered a strong CYP3A4 inhibitor in higher exposure of valbenazine and/or (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol than administration of the composition to a patient who is not being administered a strong CYP3A4 inhibitor.

62 . The composition of any one of claims 55 to 61 , wherein the patient or a medical care worker is informed that administration of the composition to a patient who is also being administered a strong CYP3A4 inhibitor may result in increased risk of one or more exposure-related adverse reactions than administration of the composition to a patient who is not being administered a strong CYP3A4 inhibitor.

63 . The composition of claim 62 , wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, increase in blood glucose, increase in weight, respiratory infections, drooling, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, increase in prolactin, increase in alkaline phosphatase, and increase in bilirubin.

64 . The composition of claim 63 , wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation.

65 . The composition of claim 64 , wherein the one or more exposure-related adverse reactions is chosen from somnolence and QT prolongation.

66 . The composition of any one of claims 55 to 65 , wherein the patient or a medical care worker is informed that co-administration of the composition and the CYP3A4 inhibitor may prolong the patient's QT interval.

67 . The composition of any one of claims 55 to 66 , wherein the patient or a medical care worker is informed that administration of the composition to a patient who is also being administered a strong CYP3A4 inhibitor may prolong the patient's QT interval than administration of the composition to a patient who is also being administered a strong CYP3A4 inhibitor.

68 . The composition of any one of claims 55 to 67 , wherein the strong CYP3A4 inhibitor is chosen from clarithromycin, chloramphenicol, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin.

69 . The composition of claim 68 , wherein the strong CYP3A4 inhibitor is chosen from clarithromycin, itraconazole, and ketoconazole.

70 . The composition of claim 69 , wherein the strong CYP3A4 inhibitor is ketoconazole.

71 . The composition of any one of claims 55 to 70 , wherein the composition is for treating a neurological or psychiatric disease or disorder.

72 . The composition of claim 71 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-refractory obsessive compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthocytosis.

73 . The composition of claim 72 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

74 . The composition of claim 73 , wherein the hyperkinetic movement disorder is tardive dyskinesia.

75 . The composition of claim 73 , wherein the hyperkinetic movement disorder is Tourette's syndrome.

76 . The composition of claim 73 , wherein the hyperkinetic movement disorder is Huntington's disease.

77 . The composition of claim 73 , wherein the hyperkinetic movement disorder is tics.

78 . The composition of claim 73 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

79 . The composition of claim 73 , wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremors.

80 . The composition of any one of claims 55 to 79 , characterized in that the composition is administered orally.

81 . The composition of any one of claims 55 to 80 , characterized in that the composition is administered in the form of a tablet or capsule.

82 . The composition of any one of claims 55 to 81 , characterized in that the composition is administered with or without food.

83 . The composition of any one of claims 55 to 82 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof.

84 . The composition of claim 83 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof.

85 . The composition of claim 84 , wherein the VMAT2 inhibitor is a valbenazine tosylate salt.

86 . The composition of claim 85 , wherein the VMAT2 inhibitor is a ditosylate salt of valbenazine.

87 . The composition of claim 83 , wherein the VMAT2 inhibitor is an isotopic variant that is L-Valine, (2R, 3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof.

88 . The composition of any one of claims 55 to 87 , characterized in that the composition is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base of the VMAT2 inhibitor.

89 . The composition of claim 88 , characterized in that the composition is administered in an amount equivalent to about 20 mg of valbenazine free base of the VMAT2 inhibitor.

90 . The composition of claim 88 , characterized in that the composition is administered in an amount equivalent to about 40 mg of valbenazine free base of the VMAT2 inhibitor.

91 . The composition of claim 88 , characterized in that the composition is administered in an amount equivalent to about 60 mg of valbenazine free base of the VMAT2 inhibitor.

92 . The composition of claim 88 , characterized in that the composition is administered in an amount equivalent to about 80 mg of valbenazine free base of the VMAT2 inhibitor.

93 . The composition of claim 88 , characterized in that the composition is administered in an amount equivalent to about 120 mg of valbenazine free base of the VMAT2 inhibitor.

94 . The composition of any one of claims 55 to 87 , characterized in that the composition is administered for a first period of time in a first amount of the VMAT2 inhibitor and then the amount is increased to a second amount.

95 . The composition of claim 94 , wherein the first period of time is a week.

96 . The composition of claim 94 or 95 , wherein the first amount is equivalent to about 40 mg of valbenazine free base.

97 . The composition of any one of claims 94 to 96 , wherein the second amount is equivalent to about 80 mg of valbenazine free base.

98 . The composition of any one of claims 55 to 87 , characterized in that the composition is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of (+)-α-DHTBZ of at least 15 ng per mL plasma over an 8 hour period.

99 . The composition of any one of claims 55 to 87 , characterized in that the composition is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of approximately between about at least 33% -50% of the C max over a 12 hour period.

100 . The composition of any one of claims 55 to 87 , characterized in that the composition is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)-α-DHTBZ per mL plasma; and (ii) a threshold concentration of at least 15 ng (+)-α-DHTBZ per mL plasma over a period of about 8 hours to about 24 hours.

101 . The composition of any one of claims 55 to 87 , characterized in that the therapeutically effective amount of the VMAT2 inhibitor is 10-90% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

102 . The composition of any one of claims 55 to 87 , characterized in that the therapeutically effective amount of the VMAT2 inhibitor is 20-80% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

103 . The composition of any one of claims 55 to 87 , characterized in that the therapeutically effective amount of the VMAT2 inhibitor is 30-70% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

104 . The composition of any one of claims 55 to 87 , characterized in that the therapeutically effective amount of the VMAT2 inhibitor is 40-60% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

105 . The composition of any one of claims 55 to 87 , characterized in that the therapeutically effective amount of the VMAT2 inhibitor is about 50% less than the amount that would be administered to a patient who is not also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

106 . The composition of any one of claims 55 to 82 , wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof.

107 . The composition of claim 106 , wherein the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt thereof.

108 . The composition of claim 106 , wherein the VMAT2 inhibitor is an isotopic variant that is (+)-α-3-isobutyl-9,10-di(methoxy-d 3 )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.